Small non-coding RNAs play crucial roles in development and disease. Globally referred to as RNA interference (RNAi), conserved small RNA pathways operate from yeast to human. They regulate gene expression, defend against viruses and control repetitive genetic elements. Additionally, their elegant mechanisms are widely harnessed for biotechnology and targeted therapy. Our group studies a particular class of small RNAs that represses transposon activity in the germline. The ability of transposons to mobilize and insert into new genomic locations threatens genomic integrity and must be suppressed. Integrity of genomic information is particularly important in germ cells that determine the genetic make-up of a species. Therefore germ cells employ specialized small RNA pathways -PIWI proteins and PIWI-interacting RNAs (piRNAs)- to silence transposons and thus ensure genomic stability and fertility in animals. Mature piRNAs guide their associated PIWI complexes to silence transposons at transcriptional or post-transcriptional levels, directing chromatin modifications or promoting RNA decay. We aim to elucidate molecular mechanisms of piRNA silencing through an integrated approach combining Drosophila genetics, biochemistry and next-generation sequencing. While recent advances have provided a framework for what resembles a small RNA-based immune system, further studies are required to elucidate the many molecular innovations that enable discrimination of transposons from host genes and efficient selective silencing of genetic mobility. Successfully meeting our goals will bolster our understanding of fundamental mechanisms that survey and guard genomic integrity.